Development and Characterization of a patient-based T-cell-therapy against HBV associated hepatocellular carcinoma

• Applicant: Dr. Janine Kah
• Subject Area: Gastroenterology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457011661

Globally, 250 million people are chronically infected with the Hepatitis B virus (HBV) and therefore display a high risk of developing hepatocellular carcinoma (HCC). In chronically infected HBV patients (CHB), HBV-specific T cells are functionally exhausted and depleted, which leads to HBV persistence and, subsequently, to HCC development.Unfortunately, HCC is most often recognized in the advanced stage of tumour progression. In this stage, multi-kinase inhibitor treatment can improve the median survival by about 2 months but is characterized by strong adverse effects.For this reason, new therapeutic options for patients with HBV-associated HCC are urgently needed.A promising therapy option could be the reactivation of the immune response by treating patients with monoclonal antibodies against blocking signals (checkpoint inhibitors) or with redirected patient-derived T cells. Checkpoint inhibitors against PD-1, such as nivolumab, can already provide a survival improvement by another 2 months. Patient-derived T cells, ex vivo modified with synthetic chimeric antigen receptors (CARs), are already used to treat acute lymphoblastic leukemia. However, both approaches exert strong adverse effects and did not show promising improvements regarding the treatment of HBV-associated HCCs so far. In contrast, the use of the natural HBV-specific T cell receptor (s-TCR) generated encouraging results by adoptive T cell transfer in humanized mice chronically infected with HBV and in patients with HBV-associated HCC, in order to develop a new therapy option.Our proposal now aims to investigate and improve the HBV-specific TCR therapy in an orthotopic-humanized HCC mouse model.

• DFG Programme: Research Grants
• International Connection: Singapore
• Cooperation Partner: Professor Dr. Antonio Bertoletti